Microporous hollow fibre membranes and flat sheet membranes are examples of microporous affinity membranes having a blood side and a filtrate side. Such membranes are well known for analytical, diagnostic or therapeutical purposes. For example, such microporous hollow fibre membranes and flat sheet membranes are useful for the treatment of blood or other biologically active fluids with a view to eliminating undesired compounds therefrom, i.e. in therapeutic apheresis. Microporous hollow fibre membranes are normally composed of a bundle of separate microporous hollow fibres. For detoxification of whole blood, e.g. dialysis and plasmapheresis, the membrane bundle is normally potted at each end of a polycarbonate tube fitted with two ports in a shell. The blood is normally extracorporeally pumped through a lumen representing the blood side, of each fibre, and a part of the blood plasma penetrates, i.e. is filtrated, through the pores of the fibre wall into an outer compartment representing the filtrate side, surrounding each fibre in the bundle. The concentrated blood containing blood cells, too large to enter the pores, and the remaining non-filtered part of blood plasma passes through the lumen. In a venous blood line the filtrated blood plasma stream is normally added to the non-filtered blood stream and returned to the patient.
With a view to eliminating undesired compounds from the blood, the surfaces and pores of the microporous affinity membranes, e.g. microporous hollow fibre membranes and flat sheet membranes, are provided with activated sites or ligands specific for binding to the undesired blood compounds to be eliminated. Such activated sites or ligands are normally based on or bound to functional groups, e.g. amino, carboxy, or sulfonic acid groups, on the microporous membrane surface. The undesired compounds to be eliminated from the blood are normally toxins of different kinds, e.g. bacterial derived toxins. Further examples of such undesired compounds are presented below.
The lumen surfaces on the blood side of microporous hollow fibre membranes, the surfaces on the blood side of flat sheet membranes, the surfaces of the pores and the surfaces on the filtrate side of such membranes are often provided with such activated sites or ligands, particularly for purification of blood or biologically active fluids.
In blood purification applications activated sites or ligands, e.g. positive amino groups as functional groups for heparin or endotoxin adsorption, on the surface on the blood side of such membranes may activate certain blood constituents, e.g. thrombocytes. In such a case, these blood constituents are activated and/or adhered to the ligands and are significantly reduced from the blood. Such an adhesion is undesired. Other blood constituents, e.g leucocytes, red blood cells and proteins, may in some extent also be adhered to such ligands or activated sites on the blood side of the membrane.
This undesired activation of blood constituents in such membranes has since long been a great problem, in particular the accompanying undesired elimination of thrombocytes from the blood. Several attempts have been made to solve this problem to prepare microporous hollow fibre membranes and flat sheet membranes lacking the above-mentioned ligands or activated sites on the blood side of the membrane, but so far only complicated processes requiring large amounts of reaction chemicals and solvents have been found. Moreover, these processes are also expensive, ineffective and not environmental friendly, thereby creating problems highly needed to solve.
WO 80/02805 describes, inter alia, a process for the treatment of and/or removal of undesired compounds from whole blood and a membrane therefor. A biologically activated material is immobilised, i.e. ligands are arranged in the pores, and/or on the surface of said membrane that faces away from said whole blood, i.e. faces the filtrate side of the membrane. Further, processes for immobilising different kinds of biologically active material, i.e. ligands, by treatment with chemicals are disclosed. Thus, an asymmetric immobilisation, i.e. creation of regioselective affinity, is disclosed with a view to avoiding contact between blood corpuscles and the immobilising reagent and, thus, pyrogen and/or anaphylactic reactions.
U.S. Pat. No. 5,868,936, WO 97/48483, U.S. Pat. No. 5,766,908, and EP-A2-0,341,413 disclose immobilising techniques for attaching ligands to the surface of the pores in hollow fibre membranes.
U.S. Pat. No. 6,090,292 discloses an asymmetric dialysis hollow fibre coated with albumin essentially on the side facing away from the blood, i.e. facing the filtrate side.
Plasma treatment is known as an effective method for modification of surfaces. It is, inter alia, used to increase the wettability and thus the adsorption properties of surfaces.
EP-A1-0,683,197, U.S. Pat. Nos. 6,022,902, 5,591,140, and 6,013,789 disclose treatment of a surface with plasma with a view to immobilising certain ligands.
U.S. Pat. No. 5,597,456 discloses atmospheric pressure plasma treatment of surfaces of medical devices.
EP-A2-0,695,622 discloses plasma modification of flat porous articles using low pressure plasma treatment.